The effects of the cell-permeable dibutyryl derivative of cyclic AMP on the vascular reactivity of isolated perfused rat lungs were examined. In lungs perfused with homologous blood, pulmonary arterial infusion of db-cAMP (30 micrograms/min) inhibited hypoxia-induced vasoconstriction (IC50 = 6.3 X 10(-5) M) and vasoconstriction due to bolus injection of angiotensin II (IC50 = 8.2 X 10(-5) M). Cyclic AMP phosphodiesterase inhibition by aminophylline acted synergistically with db-cAMP in the reduction of hypoxia-induced vasoconstriction. Somatostatin, an inhibitor of adenylate cyclase, prevented the decay of hypoxic vasoconstriction typically observed in isolated lungs, suggesting that a rise in intracellular cAMP may occur during hypoxic vasoconstriction as a consequence of activation of the adenylate cyclase. In lungs perfused with cell and protein-free salt solution, db-cAMP inhibited both initial and prolonged vasoconstriction following bolus injection of 2 microgram leukotriene C4. Thus, db-cAMP inhibited pulmonary vascular reactivity nonspecifically.